The phase relationship between the pyrazinamide polymorphs α and γ

Area of Science:

• Pharmaceutical Science
• Solid-State Chemistry
• Materials Science

Background:

• Pyrazinamide is a key drug for tuberculosis treatment, exhibiting multiple crystalline forms (polymorphs).
• Polymorphism can impact drug solubility and formulation efficacy, necessitating understanding of different crystal forms.
• Existing literature lacks defined equilibrium conditions for pyrazinamide polymorphs.

Purpose of the Study:

• To determine the temperature and pressure equilibrium conditions between pyrazinamide's alpha (α) and gamma (γ) polymorphs, liquid, and vapor phases.
• To quantify phase-change thermodynamic properties like enthalpy, entropy, and volume differences.
• To establish the thermodynamic stability relationships between pyrazinamide polymorphs under varying conditions.

Main Methods:

• Experimental determination of equilibrium temperature between α and γ polymorphs.
• Measurement of vapor pressures and solubilities for different pyrazinamide phases.
• High-pressure thermal analysis and construction of a pressure-temperature phase diagram.

Main Results:

• The equilibrium temperature between pyrazinamide α and γ polymorphs was experimentally determined to be 392(1) K.
• Form α was identified as the more stable polymorph at ambient temperature, based on vapor pressure and solubility data.
• High-pressure studies indicated that form γ becomes stable at room temperature under pressures of 260 MPa.

Conclusions:

• This research provides crucial thermodynamic data for understanding pyrazinamide's solid-state behavior.
• The findings clarify the stability of different pyrazinamide polymorphs, with implications for drug formulation and manufacturing.
• The study highlights the potential of pressure to stabilize otherwise metastable polymorphs for pharmaceutical applications.